Heparan Sulfate 6-O-Sulfotransferase Isoform-dependent Regulatory Effects of Heparin on the Activities of Various Proteases in Mast Cells and the Biosynthesis of 6-O-Sulfated Heparin

Anower-E-Khuda, Md. Ferdous; Habuchi, Hiroko; Nagai, Nobuo; Habuchi, Osami; Yokochi, Takashi; Kimata, Koji

doi:10.1074/jbc.m112.416651

Cited by 22 publications

(13 citation statements)

References 71 publications

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“…Hence, a likely explanation for the increase in mMCP6 levels in Ctr2 −/− cells could be that the increase in heparin may facilitate mMCP6 storage. In agreement with such a scenario, a previous study has shown that mMCP6 storage is severely defective in MCs lacking the expression of heparin 6-O-sulfotransferases (46). In further agreement, it is striking to note that the absence of Ctr2 led to increased expression of Hs6st1 accompanied by increased 6-O-sulfation of heparin.…”

Section: Discussionsupporting

confidence: 66%

Ctr2 Regulates Mast Cell Maturation by Affecting the Storage and Expression of Tryptase and Proteoglycans

Öhrvik

Logeman

Noguchi

et al. 2015

The Journal of Immunology

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Copper (Cu) is essential for multiple cellular functions. Cellular uptake of Cu+ is carried out by the Ctr1 high affinity Cu transporter. The mobilization of endosomal Cu pools is regulated by a protein structurally similar to Ctr1, called Ctr2. It was recently shown that ablation of Ctr2 caused an increase in the concentration of Cu localized to endolysosomes. However, the biological significance of excess endolysosomal Cu accumulation has not been assessed. Here we addressed this issue by investigating the impact of Ctr2 deficiency on mast cells, a cell type unusually rich in endolysosomal organelles (secretory granules). We show that Ctr2−/− mast cells have increased intracellular Cu concentrations and that the absence of Ctr2 results in increased metachromatic staining, the latter indicating an impact of Ctr2 on the storage of proteoglycans in the secretory granules. In agreement with this, the absence of Ctr2 caused a skewed ratio between proteoglycans of heparin and chondroitin sulfate type, with increased amounts of heparin accompanied by a reduction of chondroitin sulfate. Moreover, transmission electron microscopy analysis revealed a higher number of electron dense granules in Ctr2−/− mast cells than in wild-type cells. The increase in granular staining and heparin content is compatible with an impact of Ctr2 on mast cell maturation and, in support of this, the absence of Ctr2 resulted in markedly increased mRNA expression, storage and enzymatic activity of tryptase. Taken together, the present study introduces Ctr2 and Cu as novel actors in the regulation of mast cell maturation and granule homeostasis.

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Section: Discussionsupporting

confidence: 66%

Ctr2 Regulates Mast Cell Maturation by Affecting the Storage and Expression of Tryptase and Proteoglycans

Öhrvik

Logeman

Noguchi

et al. 2015

The Journal of Immunology

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“…In addition, the heparin chain is cleaved by a ␤-endoglucuronidase called heparanase (3). The critical steps in heparin biosynthesis involve (i) the action of NDST2 (15,17,30), (ii) the action of GLCE (31), (iii) 6-O-sulfonation by HS6st1 and HS6st2 (32,33), and (iv) GAG chain modification by HS3st1 (34,35) (Fig. 1b).…”

Section: Heparan Sulfate (Hs)mentioning

confidence: 99%

Bioengineered Chinese Hamster Ovary Cells with Golgi-targeted 3-O-Sulfotransferase-1 Biosynthesize Heparan Sulfate with an Antithrombin-binding Site

Datta

Yang

et al. 2013

Journal of Biological Chemistry

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Background: CHO-S cells produce non-anticoagulant heparan sulfate (HS) even when transfected with HS3st1 and NDST2. Results: Golgi targeting of HS3st1 alone in bioengineered CHO-S cells afforded anticoagulant HS. Conclusion: Targeting of HS3st1 to the Golgi ensured its action in biosynthesis and modified the action of other biosynthetic enzymes. Significance: Engineering the production of HS and potentially heparin could provide a safer form of this important anticoagulant drug.

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“…5 ) seem to support the idea that CS/DS-E may play a certain role in the recovery process. Expression of HS6ST-2 was markedly increased on 2 days but expression of HS6ST-1 was not, suggesting that heparin-containing mast cells may be increased in the acute stage, because HS6ST-2 but not HS6ST-1 was shown to be involved mainly in the synthesis of highly sulfated heparin [42] .…”

Section: Discussionmentioning

confidence: 95%

Mice deficient in N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase exhibit enhanced liver fibrosis and delayed recovery from fibrosis in carbon tetrachloride-treated mice

Habuchi

Ushida

Habuchi

2016

Heliyon

Self Cite

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BackgroundChondroitin/dermatan sulfate (CS/DS) rich in N-acetylgalactosamine 4,6-bissulfate (GalNAc(4,6SO4)) residues is present as decorin and/or biglycan in mouse liver, and GalNAc(4,6SO4) residues disappeared completely in N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST) knockout (KO) mice. The aim of this study was to investigate whether CS/DS rich in GalNAc(4,6SO4) residues participate in the progression or resolution of liver fibrosis.MethodsWild type (WT) and GalNAc4S-6ST KO mice were treated with CCl4 for 5 weeks. After discontinuation of CCl4 administration, histochemical and biochemical changes and expression of genes related to matrix components were compared between WT and GalNAc4S-6ST KO mice.Results and conclusionOn 2 days after cessation of CCl4 administration, higher fibrosis was observed in KO mice than in WT mice by Sirius Red staining. Serum alanine aminotransferase activity was higher in KO mice than in WT mice. Hydroxyproline contents and Sirius Red staining showed that repair of liver fibrosis in the recovery stages appeared to be delayed in KO mice. Expression of mRNA of matrix metalloproteinase (MMP)-2, MMP-13 and versican peaked at 2 days after cessation of CCl4 administration and was higher in KO mice than in WT mice. Expression of MMP-9 in the recovery stage was lower in KO mice than in WT mice. Our findings demonstrate that defect in GalNAc4S-6ST, which resulted in disappearance of CS/DS containing GalNAc(4,6SO4), appear to contribute to progression of liver fibrosis, delayed recovery from fibrosis, and various changes in the expression of proteoglycans and MMPs in carbon tetrachloride–treated mice.

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Heparan Sulfate 6-O-Sulfotransferase Isoform-dependent Regulatory Effects of Heparin on the Activities of Various Proteases in Mast Cells and the Biosynthesis of 6-O-Sulfated Heparin

Cited by 22 publications

References 71 publications

Ctr2 Regulates Mast Cell Maturation by Affecting the Storage and Expression of Tryptase and Proteoglycans

Ctr2 Regulates Mast Cell Maturation by Affecting the Storage and Expression of Tryptase and Proteoglycans

Bioengineered Chinese Hamster Ovary Cells with Golgi-targeted 3-O-Sulfotransferase-1 Biosynthesize Heparan Sulfate with an Antithrombin-binding Site

Mice deficient in N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase exhibit enhanced liver fibrosis and delayed recovery from fibrosis in carbon tetrachloride-treated mice

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